Evidence about electronic cigarettes: a foundation built on rock or sand?

All rapid responses

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RESPONSE: PHE's report addresses this study, explaining that since only EC users who have failed to quit cigarettes were recruited, efficacy is invariably underestimated. Nevertheless, dedicated EC use while smoking strongly predicts future cessation [21,22].
Multi-year cohorts and randomized trials show that using nicotine replacements, smokeless tobacco or cessation drugs together with smoking increases future smoking cessation [23-29]. It is inconceivable that ECs promote the opposite.

5. McKee and Capewell: “The recent Cochrane review… concluded that the evidence was of 'low or very low quality by GRADE standards'.”

RESPONSE: The 'low' rating (downgraded from ‘moderate’) stems from the finding that the device in one trial delivers nicotine poorly, meaning effectiveness is underestimated. The 'very low' grade relates to the randomization against NRT, not absolute efficacy.
Furthermore, the GRADE ratings are relevant only to clinical trial results, but the Cochrane Review presents many other cogent lines of evidence [30].
Additionally, PHE’s conclusion that “recent studies support the Cochrane Review findings“ is entirely ignored.

6. McKee and Capewell: “The PHE report authors concede the weakness of the evidence, noting how a single observational study with substantial limitations offers 'some of the best evidence to date on the effectiveness of EC for use in quit attempts.'”

RESPONSE: These “substantial limitations” – namely, being “unable to explore prospective predictors of quitting, including pre-quit nicotine dependence” [2] – would, if anything, bias against a positive outcome (smokers switching to EC evidently being more dependent than those confident abstaining entirely). Though, the study went beyond adjustments typically undertaken, including controlling for pre-quit dependence indirectly [31].

7. McKee and Capewell: “… a recent systematic review, which the PHE report surprisingly fails to cite, came to a different conclusion.”

RESPONSE: The mentioned review largely neglects comparing toxicant levels to tobacco smoke, or even to consider the clinical significance of findings [32], while ignoring important systematic reviews which have successfully done so [33-35].
Moreover, its misrepresentation of almost every major issue in EC toxicology include the statements:
I. “Some studies found high maximum concentrations of total TSNA”, citing studies showing TSNAs 200-1,800 times below cigarette smoke levels [36-38].
II. “Exposure to formaldehyde was comparable with smoking", referring to a study calculating formaldehyde levels nine times below that from tobacco smoke [36].
III. “Propylene glycol has been found to exacerbate and/or induce multiple allergic symptoms in children”, citing a study stating that "apparently… outcomes were not driven by propylene glycol” [39].
IV. “Values below the threshold limit don't necessarily protect against the health effect of 200–300 daily inhalations over decades”, referring to safety limits calculated for 8 hours exposures “day after day, over a working lifetime” [40].
V. “These metals appear on the U.S. Food and Drug Administration's 'Harmful and Potentially Harmful Chemicals' list”, referring to metals detected below levels acceptable to the FDA for chronic inhalation [7,41-43].

8. McKee and Capewell attack the 95% estimate for "coming from" an analysis they dismiss on basis of limitations and conflicts of interests.

RESPONSE: This is surprising considering that PHE’s report independently assesses the toxicology, concluding that the figure "appears to remain a reasonable estimate" [2].

9. McKee and Capewell: “The authors categorically dismiss the possibility that e-cigarettes may be a gateway to smoking.”

RESPONSE: They do not [2]. They explain that gateway terminology is “poorly defined”, suggesting its use be contingent upon a framework of how the theory can be tested. Tentative evidence that ECs divert youth away from smoking was also noted.
McKee and Capewell’s alleged “emerging evidence” for the gateway hypothesis uses methodology invalidated in PHE’s report.

10. McKee and Capewell: “The PHE report seems to equate lack of evidence with evidence of lack of effect. It claims that there is 'no identified risk to bystanders,' a view that may be premature.”

We agree with the published opinion by McKee and Capewell on the Public Health England’s (PHE) report [1]. The ongoing debate, however, seems to overlook e-cigarettes possible hazards by diverting the attention to potential benefit in terms of harm reduction among dual users, albeit arguable [2]. Therefore, it is essential to focus on its impact on naïve users; especially adolescents, which we intend to address here.

In the United States, e-cigarettes emergence permitted television and radio marketing of nicotine products once again, after the complete ban on tobacco products advertisement since the 1970s [3]. In 2014, around 18.3 million adolescents in the United States were exposed to at least one method of e-cigarette marketing method [4], which represents 68.9% of middle and high school students who participated in the 2014 National Youth Tobacco Survey (NYTS). More than one third of them (36.5%) were exposed to marketing messages via television. In the same survey, it was reported that e-cigarette is the leading tobacco product in use by American adolescents (lifetime and current use) [5]. In an online survey among 519 adult smokers and recent quitters, it was suggested that e-cigarette users were significantly more likely to have the urge to smoke conventional cigarettes compared to non-users after viewing e-cigarettes TV advertisement (83% and 72%, respectively) [6].

Moreover, a study among school children in Los Angeles revealed that non-smokers who used e-cigarettes were more likely to use combustible tobacco products in subsequent longitudinal follow up compared to non-users [7]. E-cigarettes supply the same addictive substance, i.e. nicotine, as in other tobacco products. Nicotine has been described as a gateway medication, not just for smoking other tobacco products, but also for alcohol and substance use [8 &9], which underscores a new paradigm of possible adverse outcomes that might be witnessed with the increasing e-cigarette use.

Furthermore, findings from a study in Utah suggest that state laws restricting sale to minors was inadequate to prevent the increasing prevalence of e-cigarette use among minors [10]. Noteworthy, the expanding use of e-cigarettes among adolescents is not confined to the USA as similar trends were observed in other countries (e.g. [11]), but data related to adolescents’ use, in general, are limited.

It can be concluded from the previous studies that e-cigarettes might lead to a rebound increase in other tobacco products use via two possible mechanisms. The first is a direct effect via the nicotine gateway mechanism [7-9]. The second, however, is an indirect one through its marketing messages [4-6], renormalization of smoking within public spaces, and societies [12]; while sale restriction alone might be ineffective in controlling adolescents’ e-cigarette increasing use [10& 13-14]. Therefore, we join the view to require regulating e-cigarette as a medication, if it has a role in smoking cessation [1&15]. This might be a reliable way to control naïve users’ (especially adolescents) access to e-cigarettes, until such reliable evidence on its safety is available.

Krupp [1] suggests that my arguments about the non-carcinogenic effects of nicotine in my previous comment [2] are rhetoric rather than scientific. However, he still uses the same laboratory (cell or animal) studies to support his opinion that nicotine has carcinogenic effects. The only exception was a case control study of exposure to nicotine insecticide. Everyone knows, however, that nicotine used in e-cigarettes and in NRTs is pharmaceutical grade (according to USP or Eur. Ph.). Additionally, he probably did not notice the 2 characteristic examples I mentioned in my previous comment about the use of extremely high levels of nicotine in laboratory experiments which are irrelevant to realistic exposure of smokers [3,4].

There is no need to performed randomized trials asking participants to use a potentially harmful substance, as Krupp suggests. There is extensive epidemiological evidence derived from the long-term use of snus. Snus provides similar, if not higher amounts, of nicotine to users on a daily basis. Sweden has a high rate of tobacco use among men, but snus use by far exceeds smoking in this population [5]. As a result, Sweden has by far the lowest rates of lung cancer and cardiovascular disease than any other European country [5]. There is extensive epidemiological evidence that snus use poses (and in many cases no) risk in developing cancer and cardiovascular disease compared to NON-SMOKERS [6-8]. Considering that snus is a tobacco product which contains some toxins, it is more than evident that nicotine is highly unlikely to significantly contribute to the minimal adverse effects caused by snus. Thus, use of cleaner nicotine-containing products (such as snus or e-cigarettes) to substitute smoking will have tremendous health benefits for smokers. This should be clearly communicated to smokers. Although the ideal scenario would be to quit smoking without using any aid or to use approved smoking-cessation medications, the vast majority of smokers fail. Thus, we are ethically obliged to provide them with less harmful alternatives. It would be unethical to mislead smokers by distorting evidence and consider cleaner nicotine-containing products as equally or more harmful than smoking.

It is concerning that scientists completely ignore human epidemiological evidence but continue to support laboratory evidence. However, even laboratory studies have never shown than nicotine is equally or more harmful than smoking. Public health, as any other scientific field, should be based on unbiased presentation of evidence.

Competing interests:
Two of my studies on e-cigarettes (unpublished yet) were performed using unrestricted funds provided to the institution Onassis Cardiac Surgery Center) by e-cigarette companies in 2013.

I read Konstantinos Farsalinos BMJ rapid response entitled ‘Evidence about nicotine toxicity and the dry puff phenomenon’ with interest[1]. He suggests that Grimsrud and others are being alarmist in contending that nicotine has an effect on cancer[2]. His only evidence appears to be recent reviews by Sanner et al and Grando that fail to present anything other than ‘laboratory studies’[2, 3]. He further argues that “in many (if not most) cases the amount of nicotine used in the experiments is by far larger than applicable to human smokers” without providing any substantiating evidence. This selective presentation of the available research misrepresents both the importance and trajectory of findings on nicotine toxicity and carcinogenicity.

Farsalinos does not mention that there are human in vivo and in vitro studies showing an association between nicotine and cancer[4, 5]. Brown et al conducted a case-control study that showed a 2.0 increased odds of reporting nicotine spray insecticide use among leukemia cases as compared to controls (95% CI: 1.2-3.4)[4]. Basu et al’s study (which appears in Grando’s review) also demonstrated that nicotine was associated with human gallbladder cancer [5]. Farsalinos also does not explain that many of the studies reviewed by Sanner et al and Grando were conducted using human tissues and provided convincing evidence that nicotine causes human DNA damage[6, 7], promoted the growth of carcinoma cells[8], and enhanced proliferation and migration of human malignant cells[9].

Studies assessing chemical toxicity or carcinogenicity are usually conducted in three ways: (a) research on accidental exposures to a substance; (b) in vitro studies using human and animal cells/cell lines; and (c) in vivo exposure involving experimental animals[10]. It would be unethical to expose people to potentially toxic or carcinogenic chemicals in order to assess safety; the lack of such studies in humans is therefore unsurprising. This pattern of omissions and misrepresentations can also be seen in Farsalinos’s contention that ‘The Lung Study’ provides evidence of the safety of nicotine replacement therapy since he does not mention the study’s limitations. The authors explain that they include confounding between historical smoking and current smoking; confounding between current smoking and current nicotine replacement; and limited exposure time (five years) that would not usually be assumed to result in cancer [11].

In conclusion, Farsalinos arguments appear more rhetorical than scientific. A thoughtful analysis of the literature describing a role for nicotine in cancer is extensive and concerning. The jury is still out on whether the nicotine concentrations and exposures found in e-cigarettes pose health risks. Evidence to date however, suggests a need for caution and further research.

The rapid response from Strongin, Peyton and Pankow of Portland State University [1] adds a note of irony and pathos to this discussion. Public Health England and many others have been increasingly concerned that public perceptions of the relative risk of smoking and vaping are wildly out of line with the best available evidence. There is now a great deal showing vaping to be much less risky than smoking [2][3]. If smokers believe that switching to vaping offers little or no risk reduction, then they may prefer to stay with the devil they know, or even to relapse back to it. But how do smokers acquire the perception that there is little or no reduction in risk? One likely explanation is the work of scientists like Strongin and colleagues, who published a research letter summarising measurements of formaldehyde hemiacetal emissions from e-cigarettes [4] claiming that:

"...long-term vaping is associated with an incremental lifetime cancer risk of 4.2×10−3. This risk is 5 times as high (...), or even 15 times as high (...) as the risk associated with long-term smoking".

Unsurprisingly this claim of elevated cancer-risk created a world-wide media storm and will have implanted the idea that e-cigarette use can have serious cancer risks - possibly more so than smoking. The only trouble is that the measurements were made in completely unrealistic conditions that no human subject would experience for more than an unpleasant instant, let alone the whole lifetime on which these cancer risk calculations were based. I and others have detailed the failings in this methodology and called for the paper to be retracted [5], making criticisms to which the authors have been unable to respond. Strongin et al’s swipe at Farsalinos et al (their reference 3) suggests they still have not assimilated the lessons of this episode. However, the damage is done, the media storm has blown through and public perceptions have been adversely altered to be further from the underlying reality. The Portland study is merely the worst of many examples of studies with flawed methodologies or misleading presentation of risk that have entered the public consciousness, originating in universities hungry for publicity and grants and then popularised and embellished in the news media hungry for sensation and internet clicks.

A responsible public health agency like Public Health England is professionally obliged to provide a counterweight to this malign dynamic. Its aim should be to ensure that public perceptions of risk and uncertainty are as closely aligned as possible to the what the science is really showing and what genuine experts assess the risks to be. In this way, it respectfully assists the public in making informed choices about their risky behaviours. This is exactly what they have done in commissioning two leading scientists in the field to provide an evidence assessment and by communicating that vaping is likely to be about 95% lower risk than smoking. If there is a legitimate criticism of the PHE’s risk communication, it is that it probably overstates the residual risks and includes a large margin for unknown future effects. Based on what is known of vapour constituents compared to cigarette smoke, it is likely that vaping is at least 95% safer than smoking and it is possible that it will have no mortal risks at all. So PHE is taking both a cautious and responsible approach, and not leaving it to the public to form their perceptions from media spin and hype.

Strongin et al incorrectly suggest that I might be in “fear of regulation" (their reference 4). I am opposed to excessive regulation or regulating these products as medicines. The simple reason for this is that piling pointless costs, burdens and restrictions onto the vaping industry simply creates regulatory barriers that protect the cigarette trade and keep smokers smoking, while shaping the regulatory regime for nicotine products to suit the business model of Big Tobacco to the exclusion of everyone else. I favour moderate regulation that improves health and safety, builds consumer confidence and removes any rogue traders or products from the market. I fear that many well-meaning public health activists do not really understand how regulation and markets interact, and that getting tough on harm reduction is little different to promoting harm.

[2] Burstyn I. Peering through the mist: systematic review of what the chemistry of contaminants in electronic cigarettes tells us about health risks. BMC Public Health 2014;14:18. doi:10.1186/1471-2458-14-18 http://www.biomedcentral.com/1471-2458/14/18

Competing interests:
Non-financial: Clive Bates is a long-standing advocate of ‘tobacco harm reduction’ as a public health strategy and has written extensively on e-cigarettes at www.clivebates.com. He was Director of the UK campaigning charity Action on Smoking and Health from 1997-2003. He receives no funding from tobacco, e-cigarette or pharmaceutical industries.

McKee and Capewell are measured voices of reason in the current climate of negativity that is promulgated by some in the e-cigarette industry, its lobbyists, users, and by some who sincerely hope that e-cigarettes will greatly reduce global tobacco addiction. The reality is that e-cigarettes will never be risk free, and so it serves no positive purpose to attack studies and discussions on e-cigarette risks and safety. The tactic of constantly shifting the entire debate to “e-cigarettes are safer than tobacco,” is a diversion from the needed discussion of the actual benefits and dangers of e-cigarette use, and it polarizes the conversation, demonizing anyone who questions the safety of e-cigarettes as undermining smokers attempting to quit tobacco.

From our experience, as well as that of others, independent researchers and public health professionals should expect to have their work taken out of context, and be subjected to aggressive trolling. [1,2] Even “harm reductionist” journal editors fuel the conspiracy theories with generalizations, accusing unnamed colleagues of ulterior motives: “bad studies on e-cigarettes are easy to do and easy to get into top journals, which are hungry for publicity. Good studies are hard to do and are difficult to get into top journals if they do not lead to scare stories.” [2]

Researchers funded by the e-cigarette industry also contribute to these issues. For example, as a result of limited trials, it has been suggested that e-cigarettes can be self-regulated by users. [3] However, it is worth remembering that the harm even from traditional cigarettes does not appear until after decades of use, as revealed by studies over large populations.

McKee and Capewell advocate evidence-based health policy via critical evaluation of all of the relevant scientific data without bias. Such an approach is not only more helpful to health practitioners than industry lobbying, but also best enables long term harm reduction.

Recently there has been much debate of various kinds about e-cigarettes and we have contributed in a small way to it (1-7). However, there is still a need for greater clarity. Succinct research based answers to the following fifteen questions may help to provide a clearer way forward.

Enjoyment
1. If a product is enjoyable and harmless why shouldn’t individuals be freely allowed to use it?

Health
2. Are e-cigarettes safer than traditional cigarettes?
3. Do e-cigarettes encourage traditional smokers to cut down or quit?
4. Is the long-term use of nicotine however used harmful?
5. Are the other ingredients used in e-cigarettes harmful?
6. Do we know the long term health consequences of e-cigarettes?
7. Are manufacturers free to add what they want to e-cigarettes?

Marketing
8. Would manufacturers promote a product that is harmful?
9. Are e-cigarettes encouraging non-smokers to smoke traditional cigarettes?
10. Are non-smokers being encouraged to smoke e-cigarettes?
11. Are sufficient steps being taken to ensure that young people are not encouraged to use e-cigarettes as a lifestyle choice?
12. Will the promotion of e-cigarettes be driven by a business or public health model or both?
13. Will the marketing of e-cigarettes in high income countries encourage people to smoke in low and middle income countries?

Research
14. Do we need more research into the efficacy and marketing of e-cigarettes?

History
15. Are there lessons to be learned from the promotion of traditional cigarettes?

It does concern me that, as a user of electronic cigarettes, I often get told by existing smokers and non-smokers that the device I am using is "as harmful as cigarettes" (Action on Smoking & Health: http://www.ash.org.uk/files/documents/ASH_891.pdf pg. 7) when in fact, as the user of said device after being a 60 a day smoker for 20 years, I can state that from my own perspective the effects of being a long-term smoker (shortness of breath, horrible coughs, lack of energy, lack of taste) have all but disappeared.

The ongoing head to head ideological "war" being conducted by Professors McKee and Capewell doesn't serve the good of the public and could in fact be considered harmful to the health and well being of the public.

I chose to smoke, and I chose to use an electronic cigarette. Those choices were mine, and mine alone. This debate, whilst far from over needs to take into account the people who are using these devices, and by extension why they are using them.

I started to smoke when I was 14, I stopped overnight when I was 40 when I bought my first e-cig.

Through my twenties & thirties I had tried to quit on numerous occasions using nearly all the cessation products and support available, but failed many times and had reached the point when I had given up giving up.

Since I switched to vaping I have persuaded smoking friends and family to switch, most have switched from smoking completely.

However in the last 12 months, something has changed, smokers are increasingly convinced that vaping is either just as bad or in some cases even worse than smoking.

I deal with serious risks on a daily basis, I know it is very difficult to precisely quantify a risk numerically but basic toxicology and nearly 10 years use in the population confirms that vaping is orders of magnitude less harmful than smoking.

To cast doubt or play down this central fact with concerns about relatively very minor and and as yet theoretical risks only leads to confusion amongst smokers. Ultimately less smokers will switch and more will die.

I'm not a scientist. I smoked for 43 yrs. and stopped after I tried my first vaporizer. It's been 15 months and I feel better. I don't know what else to say. I couldn't quit and now I have. Why can't that be enough? I'm an adult, using an adult product. I am informed.